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Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

Elevated serum urate levels cause gout, and correlate with cardio-metabolic diseases via poorly understood mechanisms. We performed a trans-ethnic genome-wide association study of serum urate among 457,690 individuals, identifying 183 loci (147 novel) that improve prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardio-metabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urateassociated loci and co-localization with gene expression in 47 tissues implicated kidney and liver as main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A trans-activated the promoter of the major urate transporter ABCG2 in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardio-metabolic traits.

A comprehensive view of sex-specific issues related to cardiovascular disease Cardiovascular disease (CVD) is the leading cause of mortality in women. In fact, CVD is responsible for a third of all deaths of women worldwide and half of all deaths of women over 50 years of age in developing countries. The prevalence of CVD risk factor precursors is increasing in children. Retrospective analyses suggest that there are some clinically relevant differences between women and men in terms of prevalence, presentation, management and outcomes of the disease, but little is known about why CVD affects women and men differently. For instance, women with diabetes have a significantly higher CVD mortality rate than men with diabetes. Similarly, women with atrial fibrillation are at greater risk of stroke than men with atrial fibrillation. Historically, women have been underrepresented in clinical trials. The lack of good trial evidence concerning sex-specific outcomes has led to assumptions about CVD treatment in women, which in turn may have resulted in inadequate diagnoses and suboptimal management, greatly affecting outcomes. This knowledge gap may also explain why cardiovascular health in women is not improving as fast as that of men. Over the last decades, mortality rates in men have steadily declined, while those in women remained stable. It is also becoming increasingly evident that gender differences in cultural, behavioural, psychosocial and socioeconomic status are responsible, to various degrees, for the observed differences between women and men. However, the interaction between sex-and gender-related factors and CVD outcomes in women remains largely unknown. CMAJ 2007;176(6):S1-44 Although cardiovascular disease (CVD) is common, significant sex-related differences in its epidemiology have only recently been appreciated. The objective of this section is to demonstrate that there are sex-specific differences in the prevalence, complications and burden of CVD in terms of mortality, hospital admissions and quality of life. Abstract Search strategyA MEDLINE search was conducted using the MeSH terms "cardiovascular disease" OR "atrial fibrillation" OR "congestive heart failure." A second search used the terms "prevalence" OR "incidence" OR "mortality" and the final search combined the results of the first 2 searches and added the terms "gender" OR "sex." Articles identified in this manner were retrieved and their reference lists searched for additional relevant articles. The search was limited to English-language publications, but no other restrictions were applied. Other data sources included Web sites of the World Health Organization, the Canadian Institute for Health Information and the National Centre for Health Statistics. Thirty-three original studies were reviewed. Studies were included if they were cohort studies, case-control studies or nested cohort studies that examined the incidence, prevalence or mortality of CVD, congestive heart failure or atrial fibrillation. The studies had to include data on both ...

Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Pressure overload induces cardiac growth in the rat, which implies the hypertrophy of cardiac muscle cells and proliferation of nonmuscle cells. The cardiac cell loss observed in parallel has generally been attributed to necrosis. Using an in situ assay, we demonstrated a phase of apoptosis or programmed cell death during the first 7 d after pressure overload with a peak at day 4 while cardiac growth continued for over 30 d. The increase in apoptosis was confirmed by quantification of 180-1500-bp DNA oligonucleosomes with agarose gel electrophoresis and in situ labeling via 3 Ј -terminal deoxynucleotidyl transferase assay. While some apoptosis was observed in the basal state in nonmuscle cells, pressure overload induced apoptosis mainly in cardiomyocytes. These data suggest that cardiac hypertrophy is initiated by a wave of apoptosis of cardiomyocytes. Thus, apoptosis may be involved in the pathogenesis of heart remodeling. ( J. Clin. Invest. 1996. 97:2891-2897.) Key words: apoptosis • heart • hypertrophy • aortic stenosis • pressure overload

OST patients with corticotropin-independent Cushing's syndrome have an adrenal adenoma or carcinoma, 1 but a few have bilateral adrenal hyperplasia. Three patients with Cushing's syndrome and corticotropin-independent bilateral adrenal hyperplasia 2-4 and two patients with adrenal adenomas 5,6 in whom food stimulated cortisol secretion have been described; the abnormal adrenal tissues in these patients aberrantly overexpressed receptors for gastric inhibitory polypeptide. 6,7 We describe a patient with Cushing's syndrome and corticotropin-independent bilateral adrenal hyperplasia in whom endogenous catecholamines, acting through an ectopic adrenal b -adrenergic receptor, stimulated cortisol secretion; the hyperadrenocorticism was inhibited by b -blockade. CASE REPORTA 56-year-old man presented with a left ileofemoral thrombophlebitis, an 8-kg weight gain, decreased libido, and sleep disturbance. Abdominal computed tomography revealed unsuspected bilateral macronodular adrenal hyperplasia (right adrenal gland, 5.2 by 4.0 by 6.0 cm; left adrenal gland, 6.5 by 6.0 by 8.5 cm). Physical examination revealed hypertension and abdominal obesity, but no cervicodorsal fat pads, abdominal striae, or muscle weakness. Urinary cortisol excretion was 711 and 1070 m g (1963 and 2953 nmol) per 24 hours (normal, 18 to 119 m g [50 to 330 nmol] per 24 hours) on two separate days. The patient's plasma corticotropin concentration was 4.3 pg per milliliter (0.86 pmol per liter; normal, 10 to 55 pg per milliliter [2 to 11 pmol per liter]) at 8 a.m. The plasma cortisol concentration was 26.2 m g per deciliter (723 nmol per liter) at 8 a.m. and 18.1 m g per deciliter (499 nmol per liter) on the morning after the administration of 2 mg of dexamethasone at midnight. The plasma aldosterone concentration, measured while the patient was supine, was 5.5 ng per deciliter (153 nmol per liter; normal, 1.0 to 16.0 ng per deciliter [27.7 to 443.8 nmol per liter]), plasma renin activity was 0.43 ng per milliliter per hour (0.12 ng per liter per second; nor-M mal, 0.50 to 1.58 ng per milliliter per hour [0.14 to 0.44 ng per liter per second]), and the plasma potassium concentration was 3.7 mmol per liter. METHODS Clinical StudiesThe studies were approved by the institutional review committee, and written informed consent was obtained from all subjects. Plasma corticotropin, cortisol, and aldosterone were measured after an overnight fast and every 30 to 60 minutes for up to 3 hours after changes in posture, intake of food or water, and the administration of several hormones and drugs. AssaysPlasma cortisol was measured by an immunofluorometric assay (Technicon Immuno I, Bayer, Tarrytown, N.Y.), corticotropin by an immunoradiometric assay (Allegro, Nichols Diagnostics, San Juan Capistrano, Calif.), and aldosterone, renin, and vasopressin by a radioimmunoassay. b -Adrenergic-Receptor Binding and Adenylyl Cyclase AssaysMembranes from adrenocortical tissues from the patient and from three patients who underwent adrenalectomy for Cushing's disease or radica...